Chaumette B1,2,3,4, Kebir O1,2,3,4, Pouch J5, Ducos B5,6, Selimi F7; ICAAR study group, Gaillard R1,2,3,4, Krebs MO1,2,3,4.
1 Universite Paris Descartes, Université Sorbonne Paris Cite, Paris, France.
2 INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, Paris, France.
3 GDR3557-Institut de Psychiatrie, Paris, France.
4 Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Paris, France.
5 Plateforme qPCR-HD-GPC, Ecole Normale Supérieure, Fondation Pierre-Gilles de Gennes, PSL Research University, Paris, France.
6 Laboratoire de Physique Statistique, Ecole normale Supérieure, PSL Research University, Université Paris-Diderot Sorbonne Paris-Cité, Sorbonne Universités Univ Paris, CNRS UMR, Paris, France.
7 Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR and INSERM U1050, Paris, France.
The biological processes associated with the onset of schizophrenia remain largely unknown. Current hypotheses favor gene × environment interactions as supported by our recent report about DNA methylation changes during the onset of psychosis. Here, we conducted the first longitudinal transcriptomic analysis of blood samples from 31 at-risk individuals who later converted to psychosis and 63 at-risk individuals who did not. Individuals were followed for a maximum of 1 year. Blood samples were collected at baseline and at the end of follow-up and individuals served as their own controls. Differentially expressed genes between the 2 groups were identified using the RNA sequencing of an initial discovery subgroup (n = 15 individuals). The most promising results were replicated using high-throughput real-time qPCR in the whole cohort (n = 94 individuals). We identified longitudinal changes in 4 brain-expressed genes based on RNAseq analysis. One of these genes (CPT1A) was replicated in the whole cohort. The previously observed hypermethylation in NRP1 and GSTM5 during the onset of psychosis correlated with a decrease in corresponding gene expression. RNA sequencing also identified 2 co-expression networks that were impaired after conversion compared with baseline-the Wnt pathway including AKT1, CPT1A and semaphorins, and the Toll-like receptor pathway, related to innate immunity. This longitudinal study of transcriptomic changes in individuals with at-risk mental state revealed alterations during conversion to psychosis in pathways and genes relevant to schizophrenia. These results may be a first step toward better understanding psychosis onset. They may also help to identify new biomarkers and targets for disease-modifying therapeutic strategies.
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1. Schizophr Bull. 2018 Feb 17. doi: 10.1093/schbul/sby009. [Epub ahead of print]
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